Enteric film and preparatoin thereof

ABSTRACT

An enteric film is produced by spraying on a material a mixed solution of (a) hydroxypropylmethylcellulose phthalate exhibiting a viscosity of about 136 to 204 centistokes as 10% methanol/dichloromethane (1:1 by weight) solution at 20° C., (b) polyethylene glycol presenting solid state at ambient temperature and (c) shellac, wherein respective ratios of (b) and (c) to (a) are 0.1 to 20 weight percent and 5 to 40 weight percent; and then drying the solution. 
     The enteric film excels in film strength and acid resistance, and can be employed in pharmaceutical preparations.

This application is a continuation-in-part of Ser. No. 412,439, filedSep. 26, 1989, now abandoned.

This invention relates to enteric films having improved strength, thusbeing usable in such fields as foods and pharmaceuticals.

Generally, enteric coating of pharmaceutical preparations has beencarried out for the purposes of the protection of the active ingredientsusceptible of the protection of the gastric juice and the drug-releasecontrolled system (or the drug delivery system). In the enteric-coatedpharmaceutical preparations, the intended purpose has been heretoforeachieved by covering tablet surfaces with the coating. In recent years,however, reports were published that the enteric-coated granules, whencompared with the enteric-coated tablets from a biopharmaceutical pointof view, do not produce individual variation in gastric emptying rateand absorption and are almost free from influence by meals, and as anexample of such granules, there may be mentioned the aspirin preparation[C. Bogentoft, et al.; Eur. J. Clin. Pharmacol., 14, 351-355 (1978) andA. Anslow et al.; Current Therapeutic Research, 36 (5), 811-818 (1984)].

Nevertheless, the conventional enteric films themselves showdeteriorated strength, and when granules being provided with the entericcoating are for example pharmaceutically processed into tablets orcapsules, such enteric coating films in many instances are destroyed dueto mechanical shock during processing and consequently fail to performthe function of the enteric coating For the prevention of such trouble,plasticizers are required to be added, but addition of plasticizersoften results in lowered effect of the enteric coating. For example, itis known that addition of polyethylene glycols tohydroxy-propylmethylcellulose phthalate brings about deterioration inthe enteric coating performance (for example, refer to the catalogue ofShin-etsu Chem. Ind., Ltd., the 1985 edition HPMCP). Under thesecircumstances an enteric film having increased film strength andadequately retaining the enteric coating property has been stronglydemanded to be developed.

Taking such situations into consideration, the present inventorsconducted intensive investigation into the coating base which is usablein the processing and manufacture of enteric granules and enteric powderhaving increased film strength and as a result: found that whenhydroxypropylmethylcellulose phthalate having specifically definedproperties, shellac and polyethylene glycol are combined at a specificratio to conduct enteric coating, there unexpectedly result entericpharmaceutical preparations with enhanced film strength and furthermorethat in cases where they are processed into other types ofpharmaceutical preparations such as tablets and capsules, suchpreparations can withstand mechanical shock or impact, thereby leadingto the completion of this invention.

Thus, this invention relates to the enteric film which is composed of(a) hydroxypropylmethylcellulose phthalate having a viscosity of about136 to 204 centistokes, (b) polyethylene glycol presenting a solid stateat ambient temperature and (c) shellac, with the mixing ratio of (b) and(c) to (a) ranging from 0.1 to 20 weight % and from 5 to 40 weight %,respectively.

Hydroxypropylmethylcelluloss phthalate (hereinafter may be referred toas "HPMCP") as used in this invention shows a methoxyl group content of18.0 to 22.0%, a hydroxypropoxyl group content of 5.0 to 9.0% and acarboxybenzoyl group content of 27.0 to 35.0%, with its mean degree ofpolymerization of about 240, and exhibits a viscosity (at 20° C.) ofabout 136 to 204 centistokes as a 10% solution (methanol/dichloromethane1:1 by weight) (refer to the Japanese Pharmacopoeia, the 11th revisededition, section concerning hydroxypropylmethylcellulose phthalate200731). Its specific examples include HP-55S (produced by Shin-EtsuChemical Co., Ltd., Tokyo, Japan).

Polyethylene glycol ( hereinafter referred to in some instances as"PEG") as used in this invention presents the solid form at ambienttemperature (15 to 25° C.) and shows normally a mean molecular weight of1,200 to 25,000, preferably 2,000 to 10,000, more preferably 7,000 to9,500. Its specific examples include PEG 1500, PEG 4000, PEG 6000 andPEG 20000.

Shellac as used in this invention is a resinous material produced bypurification/bleaching of secretions from Coccus lactis.

The process for producing enteric films according to this invention isdescribed in the following. Thus, the enteric film of this invention isobtained by covering a pharmaceutical preparation intended to beprovided with enteric property with an enteric coating agent consistingof HPMCP, PEG and shellac being formulated at the previously mentionedratio.

The pharmaceutical preparation to be covered with the said enteric filmis not specifically limited, if it includes powders, fine granules,granules (obtained by, for example, extruding granulation process orrotary granulation process), pills, tablets, capsules andpharmaceutically processed products thereof (for example, the productsproduced by processing enteric powder, enteric fine granules, entericgranules into tablets or capsules). Furthermore, the active ingredientsto be incorporated into these pharmaceutical preparations is notspecifically limited, if it can be incorporated into the preparationsfor the purpose of enteric property, and includes, for example, drugsubstances for the central nervous system, such as diazepam, idebenone,aspirin, ibuprofen, paracetamol, naproxen, piroxicam, dichlofenac,indomethacin, sulindac, lorazepam, intrazepam, phenytoin, acetaminophen,ethenzamide, and ketoprofen; cardiovascular drugs, such as molsidomine,vinpocetine, propranolol, methyldopa, dipyridamol, furosemide,triameren, nifedipine, atenolol, spironolactone, metoprolol, pindolol,captopril and isosorbide dinitrate; drugs for respiratory organs, suchas amlexanox, detromethorphan, theophilline, pseudo-ephedrine,salbutamol and guaiphenecin; drugs for digestive organs, such as drugsof benzimidazole series having anti-ulcer activity being exemplified by2-[(3-methyl-4-(2,2,2-trifluoroethoxy)2-pyridyl)methylsulfinyl]benzimidazole,(hereinafter referred to sometimes as "Compound A") and5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridyl)-methylsulfinyl]benzimidazole,cimetidine, ranitidine, pancreatin, bisacodyl and 5-aminosalicylic acid;antibiotics and chemotherapeutic agents, such as cephalexin, cephaclor,cefradine, amoxixillin, pivampicillin, bacampicillin, dicloxacillin,erythromycin, erythromycin stearate, lincomycin, doxycycline andtrimethoprim/sulfamethoxazole; drugs for the metabolic system, such asserapeptase, lysozyme chloride, adenosine phosphate, glibenclamide, andpotassium chloride; and vitamin drugs, such as vitamin B₁, vitamin B₂,vitamin B₆, vitamin C and fursulthiamin. In preparing the saidpharmaceutical preparations, there may be incorporated additives whichare generally used in processing into pharmaceutical preparations, andthe additives alone may be covered with the enteric film of thisinvention, without incorporating the active ingredient. As the additive,there may be mentioned, for example, excipients (e.g. lactose, cornstarch, sucrose, talc, crystalline cellulose, mannitol, light anhydroussilicic acid, magnesium carbonate, calcium carbonate, L-cysteine, etc.),binders (e.g. pregelatinized starch, methylcellulose,carboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, dextrin,gum arabic, low substituted hydroxypropylcellulose (hereinafter referredto sometimes as "L-HPC"), etc.), disintegrating agents [e.g. calciumcarboxymethylcellulose, starch, crosslinked sodiumcarboxymethylcellulose (hereinafter referred to sometimes as"Ac-Di-Sol"), crosslinked insoluble polyvinyl pyrrolidone, etc.],surfactants (e.g. Pluronic, Tween, polyethylene glycol, etc.),lubricants (e.g. magnesium stearate, talc, etc.), coloring agents (e.g.titanium oxide, ferric oxide, tar dyes, etc.) and the like. These agentsmay be used in more than two kinds.

As the solvent which is used to dissolve HPMCP, PEG and shellac in thisinvention, there may be mentioned, for example, mixtures of acetone andethanol and mixtures of ethanol and water, and alcohols such asisopropanol and n-propanol may be added, if necessary.

HPMCP is desirably dissolved in acetone, whereupon the mixing ratio ofHPMCP against acetone is normally 3 to 15 weight %, preferably 6 to 10weight %. A mixing ratio of less than 3 %, because of the loweredconcentration of HPMCP, requires a prolonged period of time to performthe coating in sufficient amounts enough to secure adequate entericproperty and is not preferable. A mixing ratio of not less than 20 %results in increased viscosity of the solution, bringing about troublesduring coating

PEG and shellac are desirably dissolved in ethanol, and if necessary,warming is effected in order to accelerate dissolution. Referring to themixing ratios of these substances, PEG is dissolved normally at a ratioof 0 1 to 5 weight %, preferably 0.5 to 1.5 weight %, while shellac isdissolved normally at a ratio of 1 to 10 weight %, preferably 3 to 6weight %.

The enteric coating solution is preferably produced by mixing an acetonesolution of HPMCP with an ethanol solution of PEG and shellac. When thesaid ethanol solution is mixed with the said acetone solution at a ratioof 10 to 100 weight % against the acetone solution, particularly 10 to70 weight %, there can be obtained a solution mixture free frominsoluble matter. The enteric coating solution thus mixed is sprayedonto the objective preparations to give enteric coated pharmaceuticalpreparations In reference to the composition of three substances in theenteric film of the resulting enteric coated preparation, PEG isnormally contained at a ratio of 0.1 to 20 weight %, Preferably 2 to 10weight %, while shellac usually at a ratio of 5 to 40 weight %,preferably 15 to 35 weight %, as expressed on the basis of HPMCP. Thethree-component compositions are soluble in a mixture consisting of 75to 85 weight % of alcohol and 15 to 25 weight % of water, particularlyin a mixture consisting of 78 to 82 weight % of alcohol and 18 to 22weight % of water, and when the content of HPMCP in the said mixture isnormally at a ratio of 1 to 10 weight %, with PEG and shellac beingcontained at the above mentioned ratios, excellent enteric coatingsolutions can be obtained.

Referring in more detail to the method of covering with the previouslymentioned enteric coating solution, the enteric coated tablets areobtained for example by placing plain tablets in a ventilated coatingmachine followed by spraying with the coating solution, whereby nolimitation is posed on the type of pharmaceutical Preparations to beused for coating. For this purpose, the temperature of the coatingsolution during production is not specifically required to be adjustedand may usually be at room temperature (1 to 30° C). Furthermore, in thecase of granules, for example, core granules are placed in a fluidizedcoating machine and sprayed with the coating solution withoutcontrolling the temperature of the solution as is the case with thecoating of tablets. The enteric coated preparations obtained by thisprocedure may be further treated by means of a per se known method forthe purpose of printing or polishing. Also, the enteric coated granulesand powders may be pharmaceutically processed into tablets and capsules(hard or soft capsules). In addition, they may be mixed with other typesof pharmaceutical preparations produced by a per se known process, forexample granules provided with the coating having a varied pH value ofdissolution, to give sustained release or gastrointestinal tracttargeting pharmaceutical preparations.

Below described are the examples, reference examples and test examplesto illustrate this invention more specifically, but the presentinvention is not understood to be limited by these examples.

The enteric film according to the present invention excels in filmstrength and acid resistance, and consequently, pharmaceuticalpreparations such as granules, powders and tablets can be covered withsaid enteric films to produce the enteric-coated pharamaceuticalpreparations with increased film strength.

EXAMPLE 1

Charged in a centrifugal fluidized coating granulator (CF-360,manufactured by Freund Co. of Japan) was 2100 g of Nonpareil (20 to 28mesh), and under 200 rpm rotor speed, coating was carried out throughdusting with dusting powder of the below-described composition asobtained in advance by mixing, at a rate of 20 g/minutes, while sprayingwith 2000 ml of hydroxypropylcellulose solution (3 %(v/v)) at a rate of25 ml/minute, followed by vacuum drying at 40° C. for 16 hours andsifting through a round sieve to give spherical granules having core of12 to 32 mesh.

    ______________________________________                                        [Dusting powder]                                                              ______________________________________                                        Compound A              400 g                                                 Magnesium carbonate     400 g                                                 Sucrose                 400 g                                                 Corn starch             400 g                                                 L-HPC                   60 g                                                  ______________________________________                                    

(degree of hydroxypropyl substitution: 10.0 to 13.0 % (W/W); averageparticle size not more than 30 μm. L-HPC with the same degree ofsubstitution and average particle size as described above was used inthe examples to be given in the following).

Out of the resulting spherical granules having core, 3800 g was weighedout for sampling and placed in a fluidized-bed coating machine(manufactured by Okawara Co. of Japan), and spraying was carried outwith the enteric coating solution of the following composition at a rateof 50 ml/minute, under the inlet air temperature and product temperaturebeing controlled at 60° C. and 45° C., respectively, to giveenteric-coated granules. The resulting granules were found to be almostfree from granule breaking and binding together among granules duringcoating, being covered uniformly with enteric films, and to pass theparticle size test (the particle size as granules specified in theJapanese Pharmacopeia, 11th revised edition. The same test procedure wasadopted in the examples to be described in the following) as well as theacid-resistance (the first solution) and disintegrating property (thesecond solution) tests in the disintegration test method specified inthe Japanese Pharmacopeia, 11th revised edition (the same testprocedures were adopted in the examples to be described below).

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                  780 g                                                 Polyethylene glycol 6000                                                                              8 g                                                   Shellac                 120 g                                                 Acetone                 13000 g                                               Ethanol                 2400 g                                                ______________________________________                                    

240 mg of the enteric-coated granules as obtained by the above procedurewas filled into a No. 2 hard gelatin capsule (weight: 65 mg) by use of acapsule filling machine (manufactured by Parke-Davis Co. of USA) to givea capsule. The enteric-coated granules in capsules were raken our toinvestigate into the acid resistance, with the result that there was noproblem in the property.

EXAMPLE 2

Charged in a CF granulator (manufactured by Freund Co.) was 42 g ofNonpareil (24 to 32 mesh), and under 60 rpm rotor speed, granulation wasperformed while spraying with the in-advance prepared coating solutionof the following composition at a rate of 200 ml/minute×2 guns. Thegranulated material was vacuum-dried at 40° C. for 16 hours and siftedthrough a sieve to give spherical cored granules of 12 to 32 mesh.

    ______________________________________                                        [Coating solution]                                                            ______________________________________                                               Serrapeptase   3000 g                                                         L-HPC          1600 g                                                         Lactose        160 g                                                          Sugar          1600 g                                                         Talc           1600 g                                                         Ethanol        11500 g                                                        Water          9700 g                                                  ______________________________________                                    

Out of the resulting spherical granules having core, 48 kg was weighedout and placed in a fluidized-bed coating machine (FLO-60,Freund/Okawara Co.), and spraying was carried out with the entericcoating solution of the following composition at a rate of 170o/minute×3 guns under the inlet air temperature and outlet airtemperature being controlled at 60° C. and about 40° C., respectively,to produce enteric-coated granules having a core. The resulting granuleswere found to be free from granule breaking during coating, beingcovered uniformly with enteric films, and to pass the particle size,acid resistance and disintegration tests specified in the JapanesePharmacopeia.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                  11600 g                                               Shellac                 2800 g                                                Polyethylene glycol 6000                                                                              660 g                                                 Ethanol                 56300 g                                               Acetone                 131500 g                                              ______________________________________                                    

Mixed for 3 minutes in a tumbling mixer (TM-15, manufactured by ShowaKagaku-Kikai Manufacturing Co.) were 420 g of the enteric-coatedgranules having core as obtained by the above procedure, 270 g ofaluminum hydroxide/sodium hydrogencarbonate coprecipitated product, 580g of crystalline cellulose, 150 g of crosslinked sodiumcarboxy-methylcellulose, 20 g of magnesium stearate and 1440 g of othergranules with the mixing conditions being 10 rpm for 3 minutes). Theresultant mixture was compressed into tablets at a compression pressureof 1 ton/cm², employing Pure Press Correct 19K (manufactured by KikusuiSeisakusho LTD.) with the use of an oblong type punch, to produce whiteplain tablets each having a weight of 480 mg and 15 mm of major axis,6.5 mm of minor axis, 6.4 mm of thickness and 1.2 minutes ofdisintegration time.

[Granules for tablet compression]

A mixture consisting of 900 g of acetaminophen, 7.5 g ofchlorpheniramine maleate, 48 g of noscapine, 75 g of anhydrous caffeine,24 g of dihydrocodeine phosphate, 60 g of di-methylephedrinehydrochloride 72 g of Ac-Di-Sol and 72 g of corn starch was admixed withcrystalline cellulose to make up to 1389.6 g, which was mixed adequatelyin a vertical granulator (FM-G25 type, manufactured by Fuji Sangyo Co.)(mixing conditions: 400 rpm for 10 minutes) and kneaded with an aqueoussolution of 50.4 g of hydroxypropylcellulose. The resultant whitekneaded material was dried in a fluidized-bed dryer (FD-3S, manufacturedby Fuji Sangyo Co.) at the air blowing temperature of 60° C. and passedthrough a power mill with 1.5 mmφ punching screen (P-3 type,manufactured by Showa Kagaku-Kikai Seisakusho Co.) to produce granulesfor tablet.

EXAMPLE 3

Charged into a multiplex granulator (MP-25 type, manufactured by FujuSangyo Co.) were 500 g of serrapeptase, 3000 g of sucrose, 150 g ofcrystalline cellulose, 1050 g of corn starch, 150 g of Ac-Di-Sol and 150g of hydroxypropylcellulose, and 1450 g of water was added to carry outgranulation (granulation conditions: 400 rpm for 15 minutes) Thegranulated material was subjected to fluidized drying in amulti-processor (FD-MX-1 type, manufactured by Fuji Sangyo-AeromaticCo.) at the inlet air temperature of 55° C. and sifted through a sieve,whereby the dried material of 32 to 60 mesh was sampled. 2000 g of thedried material was weighed out and placed in the previously mentionedmulti-processor (of an aero-coater type used), and spraying wasconducted with the enteric coating solution of the following compositionat a rate of 50 g/minute under the inlet-air temperature and producttemperature being controlled at about 43° C. and about 20° C.,respectively,to give enteric-coated granules The granules were found tobe free from granule breaking during coating and to be covered uniformlywith enteric films. Also, the enteric-coated granules were siftedthrough a 24 to 32 mesh screen to investigate into acid resistance, withthe result that they passed the test specified in the JapanesePharmacopeia.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                  720 g                                                 Shellac                 240 g                                                 Polyethylene glycol 6000                                                                              40 g                                                  Ethanol                 3000 g                                                Acetone                 7000 g                                                ______________________________________                                    

EXAMPLE 4

Charged into a fluidized-bed coating machine, Gratt WSG-15 (manufacturedby Gratt Co. of West Germany), was 3300 g of the spherical granuleshaving a core as used in Example 2, and spraying was performed with thefollowing enteric coating solution at a rate of 55 g/minute under theinlet-air temperature and product temperature being controlled at about55° C. and about 43° C., respectively, to give enteric coated granules.The resultant enteric-coated granules were found to be free from granulebreaking and binding together among granules during coating, beingcovered uniformly with enteric films, and to pass the particle size,acid resistance and disintegration tests specified in the JapanesePharmacopeia.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                  770 g                                                 Shellac                 187 g                                                 Polyethylene glycol 6000                                                                              44 g                                                  Ethanol                 3750 g                                                Acetone                 8770 g                                                ______________________________________                                    

EXAMPLE 5

Placed in a fluidized-bed coating machine (FD-3S, manufactured by FujiSanqvo Co.) was 550 q of the spherical granules having a core as used inExample 2, and spraying was carried out with the below-described entericcoating solution at a rate of 12 g/minute, while making the granulesfluidized at the inlet-air temperature of 60° C., to give enteric-coatedgranules. The resultant granules were found to be free from granulebreaking during coating, being covered uniformly with enteric films.Also, the enteric coated granules were sifted through a 24 to 32 meshscreen to investigate into the acid resistance, with the result thatthey passed the test specified in the Japanese Pharmacopeia.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                  140 g                                                 Shellac                 34 g                                                  Polyethylene glycol 60000                                                                             8 g                                                   Ethanol                 3350 g                                                Water                   840 g                                                 ______________________________________                                    

REFERENCE EXAMPLE 1

In the procedure of Example 4, HP-55 or HP-50 produced by ShinetsuChemical Ind. Co. of Japan. HP-55 and HP-50 show a viscosity (as a 10 %methanol/dichloromethane solution) of about 32 to 48 centistokes andabout 44 to 66 centistokes, respectively]was used in place of HP-55S toprepare enteric coating solutions, and spraying was carried out with theenteric coating solutions to produce enteric-coated granules (Controlsections 1 and 2). The resulting enteric-coated granules were found tobe free from granule breaking and binding together among granules duringcoating, being covered uniformly with enteric films, and to pass theparticle-size, acid-resistance and disintegration tests specified in theJapanese Pharmacopeia.

REFERENCE EXAMPLE 2

In the procedure of Example 4, castor oil was used in place of shellacand polyethylene glycol 6000 to prepare the following enteric coatingsolution, which was sprayed to give enteric-coated granules (Controlsection 3). The resultant enteric-coated granules were found to be freefrom granule breaking and binding together among granules duringcoating, being covered uniformly with enteric films, and to pass theparticle-size, acid-resistance and disintegration tests specified in theJapanese Pharmacopeia.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                               HP-55S         770 g                                                          Castor oil     90 g                                                           Ethanol        1980 g                                                         Acetone        7880 g                                                  ______________________________________                                    

REFERENCE EXAMPLE 3

In the procedure of Example 5, polyethylene glycol 400 or acetylatedxonoglyceride (Mybarset 9-40T), a liquid plasticiser, was used in placeof polyethylene glycol 6000 to prepare the enteric coating solution, andthe solution was sprayed to give enteric coated granules. The resultinggranules provided with enteric coating were found to be free from filmpeeling and surface roughness, being covered uniformly with entericfilms.

TEST EXAMPLE 1

The enteric-coated granules as obtained in Example 4 and ReferenceExamples 1 and 2 were mixed with crystalline cellulose at a ratio(enteric-coated granule: crystalline cellulose) of 1:2 and 1:5, and themixture was compressed into tablets each weighing about 200 mg andmeasuring 8 mmφ in outer diameter at a compression pressure of 1 ton/cm²by use of Autograph (IS-5000, manufactured by Shimadzu Seisakusho Co. ofJapan), whereby magnesium stearate was used as a lubricant. Theresulting tablets were placed in an auxiliary tube to be used in thedisintegration test for enteric-coated granules as specified in theJapanese Pharmacopeia, 11th revised edition, then shaker in the firstsolution for 60 minutes in accordance with the disintegration test forenteric-coated preparations, and the contents in the enteric-coatedgranules having remained in the auxiliary tube were measured by means ofenzymatic assay. The granules other than those covered with the entericfilms according to this invention were all found to show a greatdecrease in the contents and to be provided with enteric films ofstrength inferior to the enteric film-s of this invention.

                  TABLE 1                                                         ______________________________________                                        [Contents in enteric-coated granules]                                         Experiment     Formulation                                                                              Formulation                                         section        ratio of 1:2                                                                             ratio of 1:5                                        ______________________________________                                        Section of this                                                                              90%        98%                                                 invention                                                                     Control section 1                                                                            82%        86%                                                 Control section 2                                                                            80%        88%                                                 Control section 3                                                                            65%        66%                                                 ______________________________________                                    

TEST EXAMPLE 2

The enteric-coated granules as obtained in Reference Examples 1 and 2were compressed into tablets by the same procedure as described inExample 2. The resultant tablets were placed in an auxiliary tube in thesame manner as described in Test Example 1 and shaken in the firstsolution for 60 minutes in accordance with the disintegration test forenteric-coated granules. In the case of a beaker in which tabletsadmixed with the enteric-coated granules as obtained in Example 2 wereexamined, there was observed no granule falling down from the auxiliarytube containing enteric-coated granules, but tablets incorporated withother enteric-coated granules were found to have more than 15enteric-coated granules fall down on the bottom of the beaker from theauxiliary tube. As is evident from the above, the granules being coveredwith the enteric films of the present invention were proven to haveimproved acid resistance and increased film strength.

TEST EXAMPLE 3

In the procedure of Example 4, the formulation amount of shellac alonewas changed to 15 g and 385 g, while the one of polyethylene glycol 6000alone was changed to 231 g, to prepare three different enteric coatingsolutions, and spraying was performed with these coating solutions toproduce enteric-coated granules (Control sections 4, 5 and 6). Theresultant enteric-coated granules and the enteric-coated granules(section of this invention) as obtained in Example 4 were investigatedfor the disintegrating property and acid resistance, and as a result, itwas found that the enteric-coated granules except the ones of thisinvention failed to pass the disintegration and acid-resistance testsspecified in the Japanese Pharmacopeia, thus being unable to be used asenteric-coated granules.

                  TABLE 2                                                         ______________________________________                                        [Results of the tests of the Japanese Pharmacopeia                            on the enteric-coated granules]                                               Experiment    Disintegrating                                                  section       property    Acid resistance                                     ______________________________________                                        Section of this                                                                             ∘                                                                             ∘                                       invention                                                                     Control section 4                                                                           ∘                                                                             x                                                   Control section 5                                                                           x           ∘                                       Control section 6                                                                           ∘                                                                             x                                                   ______________________________________                                    

TEST EXAMPLE 4

The enteric-coated granules as obtained in Example 5 and ReferenceExample 3 (control sections 7 and 8) were compressed into tablets by thesame procedure as described in Example 2 (but with the compressionpressure being raised at 2 tons/cm²). The white plain tablets were allfound to weigh 480 mg, measure 15 mm in major axis, 6.5 mm in minor axisand 6 mm in thickness and have a disintegration time of about 3 minutes.The resultant tablets were subjected to the disintegration test byfollowing the same procedure as described in Test Example 1, whereuponthe contents in the enteric-coated granules having remained in theauxiliary tube were measured by means of enzymatic assay. Except thegranules covered with the enteric films of this invention, the granulesall showed a great decrease in the content and a film strength inferiorto the enteric-coated granules of this invention, as is illustrated inthe following table.

                  TABLE 3                                                         ______________________________________                                        [Contents in the enteric-coated granules]                                     Experiment section                                                                             Content                                                      ______________________________________                                        Section of this  85%                                                          invention                                                                     Control section 7                                                                              79%                                                          Control section 8                                                                              76%                                                          ______________________________________                                    

REFERENCE EXAMPLE 4

Materials having the composition ratio described below were mixed welleach other and kneaded under the addition of water.

After the kneading, the mixture was granulated by the use of extrusiongranulator (Screen diameter 1.0 mmol produced by Kikusui Seisakusho Co.,Ltd., Japan) and was processed to spherical granules employing amarumerizer (1,000 rpm; produced by Fuji Paudal Co., Ltd., Japan),vacuum dried at 40° C. for 16 hours, and sifted through a round sieve toobtain 12-42 mesh size of granules.

    ______________________________________                                        Compound A                600 g                                               Magnesium carbonate       600 g                                               Lactose                   380 g                                               Crystalline cellulose     160 g                                               Calcium carboxymethylcellulose                                                                          100 g                                               Hydroxypropylcellulose    120 g                                               Pluronic                  40 g                                                ______________________________________                                    

EXAMPLE 6

Into a fluidized-bed coating machine (produced by Okawara Co., Japan),1500 g of granules obtained in Reference Example 4 were charged andsprayed with the enteric coating solution described below undercontrolling the inlet-air temperature to 60° C. and product temperatureto 45° C. to obtain enteric granules. In order to prevent staticelectricity, 3 g of talc and 3 g of Aerosil were added to the granulesand mixed together.

    ______________________________________                                        [Enteric coating solution]                                                    ______________________________________                                        HP-55S                   310 g                                                Shellac                  62 g                                                 Polyethylene glycol 6000 18 g                                                 Talc                     36 g                                                 Titanium oxide           18 g                                                 ______________________________________                                    

REFERENCE EXAMPLE 5

Lactose granules having the compositions described below were obtainedby granulating a mixed powder of lactose, corn starch and lowsubstituted hydroxypropylcellulose making use of 10 % aqueoushydroxypropylcellulose solution in a conventional manner.

The lactose granules, enteric granules obtained in Example 6,crystalline cellulose, Ac-Di-Sol and magnesium stearate were mixed welltogether in the ratio described below and the mixture was tabletedmaking use of a rotary tableting machine (produced by Kikusui SeisakushoLtd., Japan) to obtain tablets weighing 450 mg per tablet. In thetablets each, 30 mg of Compound A is contained.

    ______________________________________                                        Lactose granules           1435 g                                             Lactose                    1056 g                                             Corn starch                264 g                                              Low substituted hydroxypropylcellulose                                                                   72 g                                               Hydroxypropylcellulose     43 g                                               Enteric granules (obtained in Example 6)                                                                 1300 g                                             Crystalline cellulose      1500 g                                             Ac-Di-Sol                  250 g                                              Magnesium stearate         15 g                                               ______________________________________                                    

We claim:
 1. An enteric film which comprises(a)hydroxypropylmethylcellulose phthalate exhibiting a viscosity of about136 to 204 centistokes as 10% methanol/dichloromethane (1 : 1 by weight)solution at 20° C., (b) polyethylene glycol presenting solid state atambient temperature and (c) shellac, the ratios of (b) and (c) to (a)being 0.1 to 20 weight percent and 5 to 40 weight percent, respectively.2. An enteric film according to claim 1, wherein the contents ofmethoxyl, hydroxypropoxyl, and carboxybenzoyl groups in thehydroxypropylmethylcellulose phthalate are 18.0 to 22 percent, 5.0 to9.0 percent and 27 to 35.0 percent, respectively, and the mean degree ofpolymerization of hydroxypropylmethylcellulose phthalate is about 240;and the polyethylene glycol presents solid state at 15 to 25° C. and hasmean molecular weight of 1,200 to 25,
 000. 3. An enteric film accordingto claim 1, wherein the polyethylene glycol is polyethylene glycol 1500,4000, 6,000 or 20,000.
 4. A process for preparing an enteric film, whichcomprises spraying on a material a mixed solution of (a)hydroxypropylmethylcellulose phthalate exhibiting a viscosity of about136 to 204 centistokes as 10% methanol/dichloromethane (1 : 1 by weight)solution at 20° C., (b) polyethylene glycol presenting solid state atambient temperature and (c) shellac, respective ratios of (b) and (c) to(a) being 0.1 to 20 weight percent and 5 to 40 weight percent; and thendrying the solution.
 5. A process according to claim 4, wherein thecontents of methoxyl, hydroxypropoxyl and carboxybenzoyl groups in thehydroxypropylmethylcellulose phthalate are 18.0 to 22 percent, 5.0 to9.0 percent and 27.0 to 35.0 percent, respectively, and the mean degreeof polymerization of the hydroxypropylmethylcellulose phthalate is about240; and the polyethylene glycol presents solid state at 15 to 25° C.and has mean molecular weight of 1,200 to 2,5000.
 6. A process accordingto claim 4, wherein the polyethylene glycol is polyethylene glycol 1500,4000, 6,000 or 20,000.
 7. A process according to claim 4, wherein thematerial is powder, fine granules, granules, pills, tablets or capsules.8. A process according to claim 4, wherein the solution is prepared byemploying a mixture of acetone and ethanol or ethanol and water as asolvent.
 9. A process according to claim 4, wherein the solution isprepared by mixing a solution of the hydroxypropylmethylcellulosephthalate in acetone and a solution of the polyethylene glycol and theshellac in ethanol.
 10. A process according to claim 9, wherein theconcentration of the hydroxypropylmethylcellulose phthalate in acetoneis 3 to 15 weight percent, the concentration of the polyethylene glycolin ethanol is 0.1 to 5 weight percent, and the concentration of theshellac in ethanol is 1 to 10 weight percent.
 11. An enteric filmaccording to claim 2, wherein the molecular weight of the polyethyleneglycol is 2,000 to 10,000.
 12. An enteric film according to claim 2,wherein the molecular weight of the polyethylene glycol is 7,000 to9,500.
 13. A process according to claim 5, wherein the molecular weightof the polyethylene glycol is 2,000 to 10,000.
 14. A process accordingto claim 5, wherein the molecular weight of the polyethylene glycol is7,000 to 9,500.
 15. A process according to claim 8, wherein the solutionadditionally contains isopropanol or normal propanol.
 16. A processaccording to claim 10, wherein the concentration ofhydroxypropylmethylcellulose phthalate in acetone is 6 to 10 weightpercent, the concentration of polyethylene glycol in ethanol is 0.5 to1.5 weight percent and the concentration of shellac in ethanol is 3 to 6weight percent.
 17. An enteric film comprising an admixture of:(a)hydroxypropylmethylcellulose phthalate exhibiting a viscosity of about136 to 204 centistokes as a 10% methanol/dichloromethane (1:1 by weight)solution at 20° C., (b) polyethylene glycol which is solid at ambienttemperature, and (c) shellac,wherein the ratios of (b) and (c) to (a)are 0.1 to 20 weight percent and 5to 40 weight percent, respectively.